Metabolism And Proteostasis: At the Intersection of Inflammation- Associated Decline in Health span

As the global research community endeavours to precipitously discover ways to prevent or treat disease in humans, attention is turning towards pursuits that will enable not only for long life, but critically longer lives that are healthy and meaningful. The process of ageing is unburdened by the evolutionary constraints that function to promote healthy procreation until around thirty years of age in humans, indicating, that along with genetics, multifactorial environmental mechanisms contribute to the ageing process of healthy individuals. Genetic models, dietary interventions, and drug treatments have all been shown to increase lifespan in mammals. But a longer life does not mean a healthier life, and to date, no discovery has even suggested immortality can be achieved in higher eukaryotes. In fact, numerous studies imply that there is an upper limit to human lifespan. There is a growing consensus that low level systemic inflammation, that is more prevalent in the elderly, and increases an individual’s chance of cardio- and neurovascular diseases associated with ageing, is the factor behind ‘healthy’ ageing. What causes this so called inflammageing is a judicious area of study, and as scientists and pharmaceutical companies develop better, broader, and more efficient treatments for human disease, greater numbers of researchers are looking to study the phenomenon of health span. At a cellular level, interventions targeting extended lifespan have given us clues as to what is occurring molecularly, for example, dietary restriction, systemically reduces metabolism, with lower levels of the proinflammatory markers that categorise inflammageing. This opinion piece will look specifically at how metabolic and proteinogenic processes dysfunction at a cellular level, to contribute to reduced health span, and how genetics, lifestyle, and therapeutics targeting these pathways are a rapidly expanding field of scientific research.

Keywords:Ageing; Health Span; Inflammation; Proteostasis; Mitochondria; Metabolism

A brief history of human ageing

The boon of immortality has been a goal of human beings since civilization began. Even though it has been shown in model organisms, including apes, that lifespan can be extended through dietary, genetic, and therapeutic modifications, there is a consensus view that for mammals’ life is finite [1]. The percentage of the human population living longer has been increasing exponentially since industrialization and the advances of modern medicine, but maximum lifespan has not [2]. With the ever-growing interventions scientific research has engendered, in the not-too-distant future humans will be able to treat/prevent most diseases/conditions that shorten life prematurely. If this is achieved it will be one of mankind’s greatest triumphs, but it will not stop us growing old, prevent the systemic health issues of the elderly, or ultimately our demise. There are underlying mechanisms that even in ‘healthy’ individuals lead to the gradual decline of physical fitness, mobility, cognitive function, and finally death [3].

Low grade systemic inflammation as a mechanism of healthspan decline

It has been understood for several decades now that proinflammatory cytokines are correlated with inflammation, and such inflammation is linked to negative health conditions associated systemically, but particularly in the cardiovascular system [4]. Initially this low-grade systemic inflammation (LGSI) throughout the ageing body was thought to be responsible for several morbidities that were the cause of cessation of life in the elderly [5]. While that is of course true, low-level inflammation has been correlated with age even in individuals without a defined pathology [6]. This could be due to undiagnosed phenotypes, cancers, conditions of the cardiovascular system, or neurological disease. Nevertheless, it has been shown that LGSI can, over a long enough period, slowly increase in extent, ultimately result in all of our deaths through physiological decline-associated ageing (PDA), which leads to systemic whole body organ failure [7]. Understanding the sources of LGSI and how we can decrease its levels and slow down its onset, is, therefore, the paradigm of current and future ageing research [8].

Lifelong cellular homeostasis: mitochondrial metabolism, endoplasmic reticulum proteinogenesis, and reactive oxygen species

The most fundamental functions of the eukaryotic cell are the molecular processes required for reading the instructions in our DNA, first as RNA species, that can have their own independent functions, then for the subset of these that encode proteins, production of the plethora of biomolecules from amino acids during translation, an essential process in all cells of our bodies from development through to old age. These processes are regulated by the cell’s nucleus and the contiguous endoplasmic reticulum (ER), the subcellular organelle where proteinogenesis and protein maturation originate. Of course, all these processes require energy, predominantly in the form of adenosine triphosphate (ATP), but also multiple other metabolites, the majority of which are produced by an ancient symbiont, that over deep time, enabled the evolution of the diverse array of complex multicellular life we have observed throughout the history of our planet, and in a comparatively short time span, ~100K years, to us, homo sapiens [9].

Mitochondria are maternally inherited, with their own genomes that encode only a handful of the mitochondrial proteome, the majority of these genes have translocated to nuclear genome over time. They function as the producers of the cofactors required as catalysts for most energy-dependent biochemical reactions. Very early on during embryonic development, there is no oxidative phosphorylation, the process of generating ATP and carbon dioxide from oxygen and water, because the embryo is in a highly hypoxic environment, ATP and other metabolic cofactors are produced through anoxic cytoplasmic glycolysis. The heart, as the first major organ to be formed during development, switches to mitochondrial metabolism as it begins to pump blood throughout the early embryo, utilizing maternal oxygen in oxidative phosphorylation [10]. During this metabolic switch mitochondria grow and spread out into a double membrane-bound network throughout the cell, with invaginations of the inner membrane, known as cristae, increasing the surface area to maximize the organelles capacity to generate ATP. This maturation process is also essential for generating the energy gradients required for respiration, whilst also allowing their outer membranes to form crucial connections with other subcellular organelles [11].

Because these fundamental processes occur in almost all of our cells, there are finely tuned signalling systems for maintaining cellular homeostasis, that require coordination between the protein maturation hub, the ER, and energy generating mitochondria. The lumen of both organelles is reliant on their oxidation/reduction status in order to perform their key cellular functions. A process which relies on the production of reactive oxygen species (ROS), highly reactive free radical-harbouring cofactors required for generation of the proton motive force, essential for oxidative phosphorylation, or protein posttranslational modifications (PTMs) in the ER, at levels that are physiological and essential for development [12]. However, increased ROS levels, a hallmark of ageing/inflammageing, can act errantly to damage biomolecules, for example mutating DNA, leading to pathology, the best-known example being tumourigenesis, but ultimately general cellular decline/senescence, and the associated age-related diseases concomitant with this [13]. Therefore, understanding how proteostasis, metabolic homeostasis, and the cross over between these two innate signalling pathways functions’, represent key processes that can be targeted in order to decrease the effects of inflammaging, and hence ageing-associated LGSI.

Interactions between the outer membranes of the two most conserved subcellular organelles

Mitochondrial-ER membrane contact sites (MERCs), formed by linker proteins on the outer membranes of both organelles, have been known for over thirty years [14]. However, their importance in regulating proteostasis, metabolism, and LGSI, has recently been recognized as crucial to PDA [15]. Understanding the molecular components and functional mechanisms through which MERCs regulate these processes is therefore key to understanding ageing. Dysfunction of MERCs has been linked to both the ER and mitochondrial unfolded protein responses [16-18], homeostatic signalling networks that respond to the improper folding of proteins, but also their maturation and PTMs. All of which are directly associated with perturbed ROS signalling [19].

The methods applied to study the biomolecular components of MERCs have been a limiting factor in allowing researchers to understand their molecular functions and the factors that regulate the levels of LGSI they are responsible for, through imbalance of ROS levels [20]. This is due to their fluid and dynamic transient nature, making their isolation from the rest of the cell’s organelles and cytoplasmic milieu experimentally complex. However, new methods that do not rely on subcellular fractionation techniques, including microscopy, both fluorescence and electron, and proximity ligation approaches [21].

Therapeutic approaches to extending health span through targeting metabolic and proteinogenic pathways

Decreasing stress on the body, be it through reducing excessive consumption, intense exercise, or energy metabolism, and importantly the strain caused through external factors on your mental wellbeing [22], are the simplest ways an individual can prevent dysfunction of these metabolic and proteostatic pathways leading to LGSI and PDA. However specific dietary changes can be followed and may lead to decreased LGSI-associated readouts, for example reducing intake of unessential protein, and intriguingly also individual amino acids, have all been linked to reduced PDA [23]. Targeted disruption of the machinery of protein synthesis has also been linked to ageing [24].

Apart from dietary and lifestyle choices, studies in model organisms have shown that compounds which interact with MERC components are currently being tested, with the hope they will increase healthspan. Such therapeutics, due to their ability to reduce LGSI, and by virtue PDA, will undoubtedly be trialled in human studies before too long. Targeting obesity/diabetes with the drug semaglutide [25], is a relevantly recent example, whereby insulin production is increase, through agonistic effects on the glucagonlike peptide 1. Interestingly, this treatment has shown promise in not only weight loss, and reduction of diabetic cases, but also the hallmarks of LGSI [26], suggesting other such compounds that act to inhibit the cellular pathways which lead to increased generalized inflammation will soon be appearing in the clinician’s arsenal.

Human ageing is, or will be, the biggest burden on the world’s healthcare systems’, and it is only going to get greater with of the number of individuals over the age of 65 predicted to be 16% by 2050 [27], due to better understanding of disease and the factors that decrease PDA. The best way to reduce this burden would be to understand as fully as possible the many factors that lead to LGSI, not to increase lifespan, but to increase healthspan, so that the world’s ageing population can be independent for longer, reducing the burden on global health and welfare systems, and promoting greater wellbeing for individuals as they age.

None.

The primary hypothesis of this study is to identify the most common chronic comorbidities among the elderly and to explore the association between age and the number of comorbidities aiming to evaluate prevalence of comorbidities in elderly patients [21-27]. The primary analysis will use descriptive analysis for demographic and exposure characteristics of the participants.

No Conflict of Interest.